Synergism between mTOR pathway and ultraviolet radiation in the pathogenesis of squamous cell carcinoma and its implication for solid-organ transplant recipients.

Nonmelanoma skin cancers (NMSCs) are the most common malignancies in the United States in immunocompetent patients. Among the solid-organ transplant recipients, NMSCs represent a significant disease burden, and they tend to be multiple and more aggressive. While the precise mechanisms responsible for the higher risk of developing cutaneous squamous cell carcinomas (SCCs) have not been completely elucidated, ultraviolet (UV) light has been established to be critical in initiation and promotion of tumor development. More recently, significant emphasis has been placed on the role of the mammalian target of rapamycin (mTOR) pathway in SCC pathogenesis. Furthermore, some studies have demonstrated the ability of mTOR inhibitors to decrease the incidence of new SCCs in the immunosuppressed transplanted patient population. In this review, we will highlight and examine the most recent available data on the role of UV radiation and its interaction with mTOR pathway signaling in SCC pathogenesis.

Therapeutic options to decrease actinic keratosis and squamous cell carcinoma incidence and progression in solid organ transplant recipients: a practical approach.

BACKGROUND: Solid organ transplant recipients (SOTRs) have a 50 to 250 times greater risk of squamous cell carcinoma (SCC) than the general population and experience higher rates of invasive and metastatic disease. These greater risks are a product of the tumorigenic effects of their immunosuppressive medications. As the number of transplantations and the life expectancy of SOTRs increase, SCCs are becoming a major source of morbidity and mortality. OBJECTIVE: To present a practical approach for busy practicing clinicians to the care of SOTRs who are developing SCCs. Topics include assessment and treatment of new and neglected SOTRs; the dermatologist's role with the transplantation team; and practical considerations in the choice of topical agents, systemic agents, and immunosuppressive therapy manipulation. METHODS AND MATERIALS: An extensive literature search of the understanding of SCC pathophysiology and treatment in SOTRs was conducted. RESULTS: Presented here is a logical, concise guide to the care of SOTRs who are developing actinic keratoses and SCCs. CONCLUSION: Proper assessment of patients, understanding therapeutic alternatives and their application, and early institution of preventative and adjuvant therapies can help to decrease skin cancer-related morbidity and mortality in SOTRs.

Prevalence of DNA Repair Gene Mutations in Blood and Tumor Tissue and Impact on Prognosis and Treatment in HNSCC.

PARP inhibitors are currently approved for a limited number of cancers and targetable mutations in DNA damage repair (DDR) genes. In this single-institution retrospective study, the profiles of 170 patients with head and neck squamous cell cancer (HNSCC) and available tumor tissue DNA (tDNA) and circulating tumor DNA (ctDNA) results were analyzed for mutations in a set of 18 DDR genes as well as in gene subsets defined by technical and clinical significance. Mutations were correlated with demographic and outcome data. The addition of ctDNA to the standard tDNA analysis contributed to identification of a significantly increased incidence of patients with mutations in one or more genes in each of the study subsets of DDR genes in groups of patients older than 60 years, patients with laryngeal primaries, patients with advanced stage at diagnosis and patients previously treated with chemotherapy and/or radiotherapy. Patients with DDR gene mutations were found to be significantly less likely to have primary tumors within the in oropharynx or HPV-positive disease. Patients with ctDNA mutations in all subsets of DDR genes analyzed had significantly worse overall survival in univariate and adjusted multivariate analysis. This study underscores the utility of ctDNA analysis, alone, and in combination with tDNA, for defining the prevalence and the role of DDR gene mutations in HNSCC. Furthermore, this study fosters research promoting the utilization of PARP inhibitors in HNSCC precision oncology treatments.

Eruptive squamous cell carcinomas, keratoacanthoma type, arising in a multicolor tattoo.

Permanent tattoos are formed through the injection of ink solids through the epidermis into the dermis and can cause multiple adverse reactions. We report a 38-year-old man who presented to our Dermatologic Surgery Unit with a diagnosis of a superficially invasive squamous cell carcinoma (SCC), keratoacanthoma (KA) type, of the left forearm in a 1-month-old tattoo. Since his initial biopsy, he developed four more similar lesions on his left forearm within his tattoo. On physical examination, the patient had a large, multicolor tattoo on his left forearm, a well-healed surgical biopsy site and four erythematous hyperkeratotic papules within differently pigmented areas of the patient's tattoo. Histopathological examination showed KA and tattoo pigment. Based on the eruptive nature of these lesions, their clinical presentation and the histopathological changes, we report this as the first case of eruptive KA arising in a multicolor tattoo.

Immobilization on graphene oxide improves the thermal stability and bioconversion efficiency of D-psicose 3-epimerase for rare sugar production.

D-Psicose (D-ribo-2-hexulose or D-allulose), an epimer of D-fructose is considered as a rare low-calorie sugar displaying important physiological functions. Enzymatic production using ketose 3-epimerases is the feasible process for the production of D-Psicose. However, major drawbacks in application of ketose 3-epimerases are bioconversion efficiency and reusability of the enzyme. We have attempted immobilization of ketose 3-epimerases from Agrobacterium tumefaciens (agtu) D-psicose 3-epimerase (DPEase) on graphene oxide. Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and Thermo gravimetric analysis (TGA) showed that the enzyme was successfully immobilized on the graphene oxide. Graphene oxide immobilized agtu-DPEase (GO-agtu-DPEase) shows pH optima at 7.5 and 60°C as higher working temperature. Significant improvement in thermal stability was observed which showed half-life of 720min at 60°C whereas Agrobacterium tumefaciens (agtu) DPEase displayed 3.99min. At equilibrium, 40:60 (D-psicose: D-fructose) the bioconversion efficiency was accounted for Graphene oxide immobilized DPEase which is higher than the agtu-DPEase. Graphene oxide immobilized DPEase showed bioconversion efficiency up to 10 cycles of reusability.

A single and two step isomerization process for d-tagatose and l-ribose bioproduction using l-arabinose isomerase and d-lyxose isomerase.

l-ribose and d-tagatose are biochemically synthesized using sugar isomerases. The l-arabinose isomerase gene from Shigella flexneri (Sf-AI) was cloned and expressed in Escherichia coli BL-21. Sf-AI was applied for the bioproduction of d-tagatose from d-galactose. l-ribose synthesis was performed by two step isomerization using Sf-AI and d-lyxose/ribose isomerase from Cohnella laevoribosii. The overall 22.3% and 25% conversion rate were observed for d-tagatose and l-ribose production from d-galactose and l-arabinose respectively. In the present manuscript, synthesis of rare sugars from naturally available sugars is discussed along with the biochemical characterization of Sf-AI and its efficiency.

Bioproduction of L-Aspartic Acid and Cinnamic Acid by L-Aspartate Ammonia Lyase from Pseudomonas aeruginosa PAO1.

Aspartase (L-aspartate ammonia lyase, EC 4.3.1.1) catalyses the reversible amination and deamination of L-aspartic acid to fumaric acid which can be used to produce important biochemical. In this study, we have explored the characteristics of aspartase from Pseudomonas aeruginosa PAO1 (PA-AspA). To overproduce PA-AspA, the 1425-bp gene was introduced in Escherichia coli BL21 and purified. A 51.0-kDa protein was observed as a homogenous purified protein on SDS-PAGE. The enzyme was optimally active at pH 8.0 and 35 °C. PA-AspA has retained 56% activity after 7 days of incubation at 35 °C, which displays the hyperthermostablility characteristics of the enzyme. PA-AspA is activated in the presence of metal ions and Mg2+ is found to be most effective. Among the substrates tested for specificity of PA-AspA, L-phenylalanine (38.35 ± 2.68) showed the highest specific activity followed by L-aspartic acid (31.21 ± 3.31) and fumarate (5.42 ± 2.94). K m values for L-phenylalanine, L-aspartic acid and fumarate were 1.71 mM, 0.346 µM and 2 M, respectively. The catalytic efficiency (k cat/K m) for L-aspartic acid (14.18 s-1 mM-1) was higher than that for L-phenylalanine (4.65 s-1 mM-1). For bioconversion, from an initial concentration of 1000 mM of fumarate and 30 mM of L-phenylalanine, PA-AspA was found to convert 395.31 µM L-aspartic acid and 3.47 mM cinnamic acid, respectively.

Bioproduction of D-Tagatose from D-Galactose Using Phosphoglucose Isomerase from Pseudomonas aeruginosa PAO1.

Pseudomonas aeruginosa PAO1 phosphoglucose isomerase was purified as an active soluble form by a single-step purification using Ni-NTA chromatography that showed homogeneity on SDS-PAGE with molecular mass ∼62 kDa. The optimum temperature and pH for the maximum isomerization activity with D-galactose were 60 °C and 7.0, respectively. Generally, sugar phosphate isomerases show metal-independent activity but PA-PGI exhibited metal-dependent isomerization activity with aldosugars and optimally catalyzed the D-galactose isomerization in the presence of 1.0 mM MnCl2. The apparent Km and Vmax for D-galactose under standardized conditions were calculated to be 1029 mM (±31.30 with S.E.) and 5.95 U/mg (±0.9 with S.E.), respectively. Equilibrium reached after 180 min with production of 567.51 µM D-tagatose from 1000 mM of D-galactose. Though, the bioconversion ratio is low but it can be increased by immobilization and enzyme engineering. Although various L-arabinose isomerases have been characterized for bioproduction of D-tagatose, P. aeruginosa glucose phosphate isomerase is distinguished from the other L-arabinose isomerases by its optimal temperature (60 °C) for D-tagatose production being mesophilic bacteria, making it an alternate choice for bulk production.

US dermatopathology fellows career survey: 2004-2005.

BACKGROUND: Graduates of a dermatopathology fellowship may choose an academic career or a career in private practice. OBJECTIVE: To assess career plans of 2004-2005 dermatopathology fellows and to correlate an academic career choice with factors identified in a national survey of US dermatopathology fellowship programs. METHODS: Surveys were mailed to 60 trainees at 45 dermatopathology fellowship programs across the United States. Pearson correlation analysis was used to interpret the data. RESULTS: Thirty-five surveys (58% response rate) were returned. Top five factors that correlated positively with an academic career choice were graduating from a non-US medical school, performing research during fellowship, importance of research in a career decision, completing a dermatology residency and publication requirement in fellowship. Top five factors that correlated positively with choosing a career in private practice were loan debt, importance of salary/earning potential, importance of job availability, being married and having an employed spouse. LIMITATIONS: Study limitations are a small sample size and potential response bias. CONCLUSION: Supporting research during fellowship, supporting applicants who completed a dermatology residency or graduated from a foreign medical school, providing loan forgiveness/repayment and increasing earning/salary potential in academic practice may encourage more young physicians to join the academic workforce.